Reframing Burkitt lymphoma: virology not epidemiology defines clinical variants

In 1964, Epstein-Barr virus (EBV) was identified in a biopsy from a patient with Burkitt lymphoma (BL) launching a new field of study into this ubiquitous human virus. Almost 60 years later, insights into the role of EBV in lymphomagenesis are still emerging. While all BL carry the hallmark c-myc translocation, the epidemiologic classification of BL (e.g., endemic, sporadic or immunodeficiency-associated) has traditionally been used to define BL clinical variants. However, recent studies using molecular methods to characterize the transcriptional and genetic landscape of BL have identified several unique features are observed that distinguish EBV+ BL including a high level of activation induced deaminase mutation load, evidence of antigen selection in the B cell receptor, and a decreased mutation frequency of TCF3/ID3, all found predominantly in EBV+ compared to EBV− BL. In this review, the focus will be on summarizing recent studies that have done in depth characterization of genetic and transcriptional profiles of BL, describing the differences and similarities of EBV+ and EBV− BL, and what they reveal about the etiology of BL. The new studies put forth a compelling argument that the association with EBV should be the defining etiologic feature of clinical variants of BL. This reframing of BL has important implications for therapeutic interventions for BL that distinguish the EBV+ from the EBV− lymphomas.